1 50 mg
+ + +
300 mg 900 mg Dibenzodiazepme
5 10 mg 20 ring Themobenzodiazepme
300 mg 750 mg Drbenzothiazepine
4mg I6mg Bciuisox.izolo
800 mgH 1200 mg Substituted benzamide
are simple dystonias and parkinsonian symptoms. Any anticholinergic agent should be withdrawn immediately. Reduction of the dose of classical antipsychotic is often advised but psychotic symptoms may then worsen or be 'unmasked'. Alternatively, an atypical antipsychotic can provide rapid improvement whilst retaining control of psychotic symptoms.
Atypical drugs, particularly at high doses, can yet cause extrapyramidal effects and this strategy is not always helpful. If the classical antipsychotic is simply continued, tardive dyskinesia remits spontaneously in around 30% of patients within a year but since the condition is difficult to tolerate, patients may be keen to try other medications, even where evidence suggests that the success rates for remission are limited. These include vitamin E, benzodiazepines, (3-blockers, bromocriptine and tetrabenazine. Clozapine, which does not appear to cause tardive dyskinesia, may be used in severe cases where continuing antipsychotic treatment is required and symptoms have not responded to other medication strategies.
Cardiovascular effects. Postural hypotension may result from blockade of a-adrenoceptors; it is dose-related. Prolongation of the QT interval in the cardiac cycle may rarely lead to ventricular arrhythmias and sudden death (but particular warnings and constraints apply to the use of thioridazine and pimozide).
Prolactin elevation. Classical antipsychotics raise plasma prolactin concentrations by their blocking action on dopamine receptors in the tuberoinfundi-bular pathway (Fig. 19.3 and p. 711) and can cause gynaecomastia and galactorrhoea in both sexes, and menstrual disturbances. A change to an atypical agent such as quetiapine or olanzapine (but not risperidone or amisulpride) should minimise these effects. If continuation of the existing classical antipsychotic is obligatory, a dopamine agonist such as bromocriptine or amantadine may be beneficial.
Sedation. In the acute treatment of psychotic illness this may be a highly desirable property but it may be unwelcome as the patient seeks to resume work, study or relationships.
Classical antipsychotics may also be associated with:
• weight gain (a problem with almost all classical antipsychotics with the exception of loxapine, most pronounced with fluphenazine and flupentixol)
• seizures (chlorpromazine and thioridazine are especially likely to lower the convulsion threshold)
• interference with temperature regulation (hypothermia or hyperthermia, especially in the elderly)
• sexual dysfunction (ejaculatory problems through a-adrenoceptor blockade)
• retinal pigmentation (chlorpromazine, thioridazine, vision is affected if dose is prolonged and high)
• corneal and lens opacities
• blood dyscrasias (agranulocytosis and leucopenia)
• osteoporosis (associated with prolactin elevation)
• jaundice (including cholestatic).
Atypical drugs can provoke a range of adverse effects that is similar to that of the classical antipsychotics but is generally lesser in degree (with exceptions). The following are the main differences.
Atypical antpipsychotics provoke fewer extrapyramidal effects (less blockade of dopamine D2-receptors in the nigrostriatal pathway). Nevertheless, extrapyramidal effects are seen, notably with high dose of risperidone (8-12 mg per day) and olanzapine (> 20 mg/day).
Clozapine and olanzapine are the most likely of the atypical agents to cause anticholinergic (anti-muscarinic) effects. They are more likely than other atypicals to cause weight gain (glucose tolerance may be impaired and should be monitored in susceptible individuals) and are second only to quetiapine in their sedative effects. Sexual dysfunction and skin problems are rare with atypical antipsychotics. Risperidone and amisulpride are as likely as classical antipsychotics to raise prolactin concentrations and cause galactorrhoea.
Clozapine warrants further mention, given its value for patients with treatment-resistant schizophrenia or severe treatment-related extrapyramidal symptoms. It may cause postural hypotension and tachycardia, and provoke seizures in 3-5% of patients at doses above 600 mg/day. Most important is the risk of agranulocytosis in up to 2% of patients (compared with 0.2% in classical antipsychotics). When clozapine was first licenced without requirements for regular white count monitoring, the haematological problems caused appreciable mortality. Thanks to strict monitoring, there have been no recorded deaths from agranulocytosis since clozapine was reintroduced in the United Kingdom, and internationally the death rate among the small minority who develop agranulocytosis is now less than 1 in 1000.
The syndrome may develop in up to 1% of patients using antipsychotics and is more prevalent at high doses. The elderly, and those with organic brain disease, hyperthyroidism or dehydration are thought to be most susceptible. Clinical features include:
• confusion or fluctuating consciousness
• rigidity of muscles which may become severe
• autonomic instability manifest by labile blood pressure
• urinary incontinence or retention.
Raised plasma creatine kinase concentration and white cell count are suggestive (but not conclusive) of neuroleptic malignant syndrome. There is some clinical overlap with the 'serotonin syndrome' (see p. 376) and concomitant use of SSRI antidepressants (or possibly TCAs) with antipsychotics may increase risk.
It is essential to discontinue the antipsychotic when the syndrome is suspected and to be ready to transfer the patient to a medical ward for rehydration. Benzodiazepines are indicated for sedation and their transquillising effect may be useful where active psychosis has to be left untreated. Dopamine agonists (bromocriptine, dantrolene) are beneficial in some cases. There is also evidence to support a role for electroconvulsive therapy in treatment of neuroleptic malignant syndrome. Even when recognised and treated, the condition carries a mortality of 12-15%, through cardiac arrhythmia, rhabdomyolysis or respiratory failure. The condition usually lasts for 5-7 days after the antipsychotic is stopped but may continue longer when a depot preparation has been used. Fortunately those who survive tend to have no long lasting physical effects from their ordeal.
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